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ItemUnderstanding the indirect effects of pneumococcal conjugate vaccines in the Asia-Pacific regionChan, Jocelyn Yuen-Wai ( 2021)Pneumococcal disease is a leading cause of childhood morbidity and mortality worldwide. Pneumococcal conjugate vaccines (PCV) protect against disease through direct effects on vaccinated individuals and indirect (herd) effects on the wider community. These indirect effects have been integral to the success of PCVs. In addition to comprising a substantial component of overall vaccine impact, the introduction of PCVs in childhood immunisation programs have also enabled near elimination of vaccine-type (VT) pneumococcus in many high-income countries. However, little is known about the PCV coverage required to achieve substantial indirect effects. The objective of this thesis was to document the indirect effects of PCV and investigate the relationship between PCV coverage and indirect effects in a variety of settings with contrasting pneumococcal epidemiology. The study presented in Chapter 2 identified substantial indirect protection against pneumococcal disease at low levels of PCV coverage across diverse settings in Australia, challenging assumptions that high PCV coverage is required for indirect effects. However, high rates of PCV coverage remained important for achieving near elimination of invasive pneumococcal disease (IPD) due to vaccine serotypes. The second part of the thesis (Chapters 3-6) focusses on the indirect effects of PCV among low- and middle-income countries (LMICs). While the indirect effects of PCV have been well-established in high-income countries, evidence is limited in LMICs where IPD surveillance can be challenging to implement. In Chapter 3, I reviewed the role of pneumococcal carriage studies as an adjunct to disease surveillance for the evaluation of PCVs in LMICs. Carriage surveillance is less resource-intensive to establish compared to IPD surveillance and is well-suited to monitoring indirect effects, since the indirect effects PCV are mediated by reductions in VT carriage and transmission. Reductions in VT carriage are expected to translate into reductions in VT disease, since carriage is a prerequisite for disease. Chapters 4, 5 and 6 relate to a multi-site prospective observational study to investigate the relationship between PCV coverage and indirect effects on VT carriage among children hospitalised with acute respiratory infection in Lao People’s Democratic Republic (Lao PDR), Mongolia and Papua New Guinea. The published protocol for the study is presented in Chapter 4, while Chapters 5 and 6 report results from Lao PDR and Mongolia respectively. In both Lao PDR and Mongolia, my analyses found a clear association between PCV coverage and indirect effects against VT carriage. In Lao PDR (Chapter 5), indirect effects were observed despite low and heterogenous PCV coverage at the village level. The adjusted model predicted a relative decrease of 36.0% in VT carriage (from 20.0% to 12.8% among children under five years) associated with increases in PCV13 coverage from zero to 60% in the same age group. In Mongolia (Chapter 6), indirect effects were observed among children from both formal settlements (comprised of houses and apartments) and informal settlements (comprised of temporary dwellings [gers]). Overall, the model predicted a relative decrease of 55% VT carriage among children under five years of age, from 29.1% to 13.1% as PCV coverage reached 100% in the same age group. Overall, the studies highlight how the association between PCV coverage and indirect effects are context dependent. The degree of indirect effects observed at comparable levels of PCV coverage varied considerably across settings. Potential explanations include differences in surveillance methods, vaccine type, vaccine schedule and background pneumococcal epidemiology. While the benefits of indirect effects commence at low level of PCV coverage across a variety of settings, control of VTs may not be achievable despite high levels of PCV coverage in some settings. These findings have important relevance for the use of reduced dose schedules, which are a global research priority since they have the potential to substantially reduce program costs while maintaining vaccine impact. However, reduced dose schedules, which comprises of two rather than three doses, are only suitable for use in settings that have achieved control of VTs. Alternative strategies to maximise indirect effects, such as targeting of older age groups or use of schedules with higher efficacy, may be required in settings that have failed to achieve control of VTs despite high PCV coverage. Further research is needed to develop and evaluate vaccination strategies for high pneumococcal burden settings.